Mechanism behind miRNA's Ability to Shut Down Protein Production Revealed

Johns Hopkins scientists believe they may have figured out how miRNAs are able to stop the production of some proteins. In both computer and test-tube studies using fruit-fly protein, the team found that miRNAs direct Argonaute proteins to specific target mRNAs to repress protein expression.

The research appeared in the January edition of Nature Structural & Molecular Biology in a paper titled “MicroRNA assassins: factors that regulate the disappearance of miRNAs.”

The Johns Hopkins group studied Argonaute because it is known to bind to miRNA and ultimately shut down protein production. Previous studies have been inconclusive about the mechanism by which miRNAs bound to Argonautes prevented the production of protein from a given gene.

The team set out to characterize Argonautes first using computers to compare their shapes and structures with other proteins. They found striking similarities between Argonaute structures and proteins that happened to exhibit allostery, a condition in which the binding of one molecule stimulates the binding of a second.

By chopping up Argonaute proteins from fruit flies and testing each piece individually, the team showed that allostery stimulated 10-fold the binding of the Argonaute and miRNA complex to mRNA.

The scientists speculate that as a result of being bound, the mRNA was prevented from doing its job of delivering a gene's instructions to the ribosome that translates them and manufactures proteins.

“MicroRNAs are all the rage,” points out Rachel Green, Ph.D., a Howard Hughes Medical Institute investigator and professor of molecular biology and genetics in the Johns Hopkins University School of Medicine. “Suddenly, in the last 10 years there's this whole set of genes and cellular components that we had no idea existed, and they're ubiquitous. They play roles in all manner of development, and Argonautes are the main class of protein involved in regulating them.”